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Module 2.7.2 — Summary of Clinical Pharmacology Studies (TILA-278)

Field	Value
Document ID	M2.7.2
Version	1.0
Compound	TILA-278 (anti-TL1A antagonist / IL-22R agonist bispecific)
Standard	ICH M4E / E3
Confidentiality	Confidential

CTD summary for the TILA-278 program; clinical figures trace to Study TILA278-201.

Change History

Version	Date	Author	Summary
1.0	2026-07-08	Clinical/Regulatory	Initial issue

2.7.2 Summary of Clinical Pharmacology Studies

This summary integrates the clinical pharmacology of TILA-278, a humanized IgG1 bispecific monoclonal antibody in which one Fab arm antagonizes TL1A (TNFSF15) and the second arm acts as an agonist at the IL-22 receptor, administered subcutaneously (SC) for the treatment of moderate-to-severe ulcerative colitis (UC). The dual mechanism is complementary: TL1A antagonism attenuates TH1/TH17-driven mucosal inflammation and intestinal fibrosis, while IL-22 receptor agonism promotes intestinal epithelial regeneration and mucosal-barrier repair. The clinical pharmacology data package characterizes TILA-278 pharmacokinetics (PK), which are dominated by target-mediated drug disposition (TMDD); the relationship between exposure and both efficacy and safety; immunogenicity and its impact on PK, efficacy, and safety; the influence of intrinsic and extrinsic factors; and the resulting dose-selection rationale for the Phase 3 program. Individual study reports are provided in Module 5.3; the tabulated PK and immunogenicity data underpinning the population analyses are in Modules 5.3.3 and 5.3.5. This section should be read together with the Summary of Biopharmaceutic Studies (2.7.1), the Summary of Clinical Efficacy (2.7.3), and the Summary of Clinical Safety (2.7.4). Nonclinical pharmacokinetics and pharmacology are summarized in Modules 2.6.2 (Pharmacology) and 2.6.4 (Pharmacokinetics).

2.7.2.1 Background and Overview

TILA-278 drug product is a sterile solution for SC injection supplied in a single-use prefilled syringe/autoinjector (formulation buffer with polysorbate; see Module 3.2.P). As a large-molecule immunoglobulin, TILA-278 is eliminated by proteolytic catabolism and by target-mediated pathways rather than by hepatic cytochrome P450 (CYP) metabolism or renal excretion of intact antibody. Because TILA-278 engages two human-specific targets, its disposition is expected to be governed by binding to, and turnover of, both TL1A and the IL-22 receptor, producing nonlinear, dose- and concentration-dependent clearance at sub-saturating concentrations. This mechanistic expectation framed the clinical pharmacology strategy: (i) a first-in-human study in healthy adults to establish single- and multiple-dose SC PK, absolute bioavailability, dose-exposure characteristics, and preliminary immunogenicity; (ii) a population PK (popPK) analysis integrating dense and sparse concentration data with the Phase 2b patient data to quantify disposition, TMDD, and covariate effects; and (iii) exposure-response (E-R) analyses for efficacy and safety and an integrated immunogenicity assessment to support Phase 3 dose selection.

The clinical pharmacology evidence contributing to this summary is listed in Table 2.7.2-1.

Table 2.7.2-1. Clinical pharmacology studies and analyses contributing to Module 2.7.2

Study / Analysis	Design	Population	Key clin-pharm objectives
TILA278-101	Phase 1, randomized, double-blind, placebo-controlled SAD/MAD; SC cohorts with one IV reference cohort	Healthy adults (N=64)	Single/multiple-dose SC PK, absolute bioavailability, dose-exposure relationship, initial safety/immunogenicity
TILA278-201	Phase 2b, randomized, double-blind, placebo-controlled, parallel-group, 12-week induction	Moderate-to-severe UC (900 randomized)	Sparse PK, target-engagement biomarkers, immunogenicity, E-R for efficacy and safety
PMx-PK-001 (popPK)	Nonlinear mixed-effects analysis (parallel linear + TMDD elimination)	Pooled TILA278-101 + -201	Structural disposition model, TMDD parameters, intrinsic/extrinsic covariates
PMx-ER-001 (exposure-response)	Logistic/E<sub>max</sub> E-R and AE-exposure analyses	TILA278-201 active + placebo	Quantify E-R for remission/Mayo and for safety

Bioanalytical methods. Serum TILA-278 concentrations were measured with a validated ligand-binding assay detecting the intact bispecific antibody via both target-capture arms, with a lower limit of quantification (LLOQ) of 0.05 µg/mL. Free (unbound) TL1A and IL-22-pathway pharmacodynamic markers were measured with validated immunoassays. Anti-drug antibodies (ADA) were assessed using a tiered, validated electrochemiluminescence bridging format (screening → confirmatory → titre), with neutralizing antibodies (NAb) evaluated by a competitive ligand-binding assay configured to detect neutralization at each functional arm; assay sensitivity was approximately 100 ng/mL with acceptable drug tolerance at anticipated therapeutic trough concentrations. Method validation reports are in Module 5.3.1.4.

2.7.2.2 Summary of Results of Individual Studies

2.7.2.2.1 TILA278-101 — First-in-human single- and multiple-dose study (healthy adults)

Following single SC administration across the 30–600 mg range, TILA-278 was slowly absorbed, with median time to maximum concentration (t_max) of approximately 6 days (range 4–8) and a mean absolute SC bioavailability of approximately 64% estimated against the IV reference cohort. Systemic exposure (C_max, AUC) increased in a greater-than-dose-proportional manner across the lower portion of the dose range and approached dose-proportionality at higher doses, consistent with saturable, target-mediated elimination. The apparent terminal half-life was concentration-dependent, ranging from approximately 6–9 days at low, sub-saturating concentrations to approximately 15–18 days at higher concentrations where target-mediated clearance was largely saturated and elimination approached the first-order catabolic rate typical of an IgG1 antibody. Repeat SC dosing produced predictable accumulation. Single and multiple SC doses were well tolerated; treatment-emergent ADA were infrequent and of low titre, with no impact on the safety profile in healthy volunteers. These data established the anticipated clinical dose range and the TMDD framework carried into the patient population.

2.7.2.2.2 TILA278-201 — PK, biomarker, and immunogenicity results (UC patients)

TILA278-201 was a Phase 2b, randomized, double-blind, placebo-controlled, parallel-group 12-week induction study (Protocol TILA278-201). Of 1700 subjects screened, 900 were randomized 1:1:1 to TILA-278 High (450 mg SC; n=299), TILA-278 Low (150 mg SC; n=300), or placebo (n=301), stratified by baseline modified Mayo severity and prior biologic exposure. Study drug was administered SC at Weeks 0, 2, 4, and 8, with study visits at Weeks 0, 2, 4, 8, and 12 and the primary efficacy assessment at Week 12. Sparse serum PK samples (pre-dose/trough and selected post-dose) and immunogenicity samples were collected at scheduled visits; a subset participated in enriched sampling to support the disposition model.

Observed trough concentrations were dose-ordered and consistent with the popPK predictions in Section 2.7.2.3. Target-engagement and downstream pharmacodynamic markers (Section 2.7.2.3.3) confirmed dose-dependent TL1A neutralization and IL-22-pathway activation in the target population. Efficacy and safety outcomes from this study are summarized in 2.7.3 and 2.7.4 and are used here as the anchors for the E-R analyses.

2.7.2.3 Comparison and Analyses of Results Across Studies

2.7.2.3.1 Pharmacokinetics

Absorption. After SC administration, TILA-278 is absorbed slowly into the systemic circulation, predominantly via lymphatic uptake, with a first-order absorption rate constant (k_a) of approximately 0.27 day⁻¹ and median t_max of 5–7 days. Absolute SC bioavailability is approximately 63%. No clinically relevant effect of injection site (abdomen, thigh, or upper arm) on absorption was identified (Section 2.7.2.3.7).

Distribution. TILA-278 distributes into a volume approximating the plasma and interstitial space, with a central volume of distribution (V_c) of approximately 3.1 L and a volume of distribution at steady state of approximately 5.7 L, typical of an IgG1 antibody and consistent with limited extravascular penetration.

Elimination and target-mediated disposition. Elimination occurs by two parallel routes: a linear, nonspecific catabolic pathway (Fc-mediated, FcRn-recycled proteolytic turnover) and a saturable, target-mediated pathway reflecting binding to and internalization with TL1A and the IL-22 receptor. At low, sub-saturating serum concentrations the target-mediated route contributes disproportionately to total clearance, producing rapid, nonlinear elimination; as concentrations rise and targets become saturated, total clearance decreases toward the linear catabolic value and the effective half-life lengthens. Across the clinically relevant 150–450 mg range, targets are substantially saturated over most of the dosing interval, so exposure increases approximately in proportion to dose and the terminal phase is governed largely by the linear, FcRn-recycled catabolic route; the effective (accumulation) half-life over the induction dosing interval is approximately 14 days, within the range expected for an IgG1 antibody. No intact antibody is expected in urine, and hepatic CYP metabolism does not contribute to elimination.

Accumulation. With the Q2W-to-Q4W induction schedule (Weeks 0, 2, 4, 8), modest accumulation was observed, with an accumulation ratio of approximately 1.6–2.0 by Week 8; steady-state-like conditions were approached by Week 8 in most subjects.

Predicted steady-state exposures by dose are summarized in Table 2.7.2-2.

Table 2.7.2-2. Model-predicted steady-state exposure by dose (TILA278-201 induction regimen)

Parameter (steady state)	TILA-278 Low (150 mg SC)	TILA-278 High (450 mg SC)
C<sub>trough,ss</sub> (µg/mL)	4.9	17.8
C<sub>avg,ss</sub> (µg/mL)	8.6	28.0
C<sub>max,ss</sub> (µg/mL)	14	42

Values are population geometric means. Approximate dose-proportionality across this range reflects near-saturation of target-mediated clearance.

2.7.2.3.2 Population Pharmacokinetics

The disposition of TILA-278 was described by a two-compartment model with first-order SC absorption and parallel linear (first-order) plus saturable Michaelis-Menten elimination, implemented as a quasi-steady-state approximation of TMDD to capture the two-target system parsimoniously. The model adequately described both the healthy-volunteer and patient data across the dose range, and predictive checks supported its use for E-R and dose-projection analyses. Population parameter estimates are summarized in Table 2.7.2-3.

Table 2.7.2-3. Population pharmacokinetic parameter estimates

Parameter	Estimate	Interpretation
CL (linear)	0.19 L/day	Nonspecific catabolic clearance
V<sub>c</sub>	3.1 L	Central volume
V<sub>p</sub>	2.6 L	Peripheral volume
Q	0.62 L/day	Inter-compartmental clearance
k<sub>a</sub>	0.27 day⁻¹	SC absorption rate
F	0.63	Absolute SC bioavailability
V<sub>max</sub>	0.9 mg/day	Maximum target-mediated elimination rate
K<sub>m</sub>	0.35 µg/mL	Concentration at half-maximal target-mediated elimination

Inter-individual variability was moderate for clearance and central volume. The covariates found to significantly influence exposure are described in Sections 2.7.2.3.6 and 2.7.2.3.7 and were retained where they improved model fit; none, individually or in combination, produced exposure changes judged to warrant dosing adjustment.

2.7.2.3.3 Pharmacodynamics and Biomarkers

Target engagement was consistent with the bispecific mechanism and was dose-ordered. On the TL1A-antagonist arm, free (unbound) serum TL1A was suppressed by more than 90% throughout the dosing interval at the High dose and by approximately 75–85% at the Low dose, indicating near-complete TL1A neutralization at High-dose exposures. On the IL-22 receptor-agonist arm, serum markers of IL-22-driven epithelial regeneration (e.g., REG3A/REG1B) increased in a dose-ordered fashion, consistent with pharmacologically active agonism at the achieved concentrations. Downstream disease-activity biomarkers reinforced the mechanism: reductions in faecal calprotectin and C-reactive protein (CRP) at Week 12 were dose-ordered (High > Low > placebo), aligning with the mucosal anti-inflammatory (TL1A) and barrier-repair (IL-22) actions. Together, these data indicate that the High dose maintains near-maximal TL1A neutralization together with robust IL-22-pathway activation across the dosing interval, whereas the Low dose provides incomplete and less sustained target coverage.

2.7.2.3.4 Exposure-Response for Efficacy

Efficacy in TILA278-201 was clearly dose-ordered, providing the anchor for the E-R analysis. In the full analysis set, the LS-mean change in modified Mayo score at Week 12 (ANCOVA) was −3.36 for High, −2.76 for Low, and −1.00 for placebo; the placebo-adjusted differences were −2.36 (95% CI −2.49, −2.23; p<0.0001) for High and −1.77 (95% CI −1.90, −1.64; p<0.0001) for Low. The primary endpoint, clinical remission (modified Mayo ≤2 with no subscore >1) at Week 12, was achieved by 37.3% (106/284) of High, 16.2% (46/283) of Low, and 0.7% (2/273) of placebo subjects — a monotonic, dose-ordered relationship.

Linking these outcomes to individual model-predicted exposures, the probability of clinical remission increased with steady-state average concentration (C_avg,ss) and trough concentration. An E_max-type logistic E-R model described the relationship, with a model-estimated C_avg,ss associated with half-maximal effect (EC50) of approximately 12 µg/mL. The Low-dose C_avg,ss (≈8.6 µg/mL) falls on the steep, ascending portion of the curve, whereas the High-dose C_avg,ss (≈28 µg/mL) lies on the upper, flattening portion approaching the exposure associated with near-maximal response — consistent with the large incremental remission gain from placebo to Low and the more modest, plateauing gain from Low to High. The quartile analysis of exposure versus remission (active-treated subjects, with placebo as reference) is shown in Table 2.7.2-4.

Table 2.7.2-4. Clinical remission at Week 12 by steady-state exposure quartile

Exposure group (C<sub>avg,ss</sub>)	Clinical remission, %
Placebo (reference)	0.7
Q1 (<7 µg/mL)	11.3
Q2 (7–14 µg/mL)	19.7
Q3 (14–24 µg/mL)	31.5
Q4 (>24 µg/mL)	41.2

Observed remission rates trend with exposure and bracket the dose-group results (Low 16.2%, High 37.3%).

The concordance of dose, exposure, target engagement, pharmacodynamic biomarkers, and clinical remission supports a causal, exposure-driven efficacy relationship rather than a chance dose ordering.

2.7.2.3.5 Exposure-Response for Safety

TILA-278 was well tolerated, and no positive systemic exposure-toxicity relationship was identified. In TILA278-201 (Safety Analysis Set), the proportions of subjects with ≥1 treatment-emergent adverse event (TEAE) were 109/284 (38.4%) for High, 131/283 (46.3%) for Low, and 130/273 (47.6%) for placebo; serious adverse events (SAEs) occurred in 3, 0, and 4 subjects and deaths in 2, 0, and 1 subjects (High/Low/placebo), respectively, with all deaths assessed as unrelated to study drug. Study discontinuations were 17/17/29 (High/Low/placebo), the higher placebo rate being driven by lack of efficacy. The active High-dose group did not show a higher overall TEAE rate than the Low-dose or placebo groups; if anything, the overall TEAE rate was lower at the higher dose, reflecting the higher frequency of disease-activity-driven events (worsening UC, anaemia) among less effectively treated, lower-exposure subjects.

The most frequent adverse events were nasopharyngitis, headache, worsening UC (more frequent on placebo, reflecting disease activity), anaemia, arthralgia, upper respiratory tract infection, injection-site reaction, and nausea. When overall TEAE frequency was arrayed against model-predicted steady-state exposure quartile among active-treated subjects, the relationship was inverse rather than positive (Table 2.7.2-5), tracking disease control rather than a toxic effect of drug. The one adverse-event category more frequent at higher exposure was local injection-site reactions — the principal drug-attributable finding — reported in 8.1% (23/284) of High-dose, 6.0% (17/283) of Low-dose, and 1.1% (3/273) of placebo subjects. These reactions were predominantly mild, local, self-limited, and non-serious, did not lead to discontinuation, and their modest exposure dependence is an expected feature of SC antibody administration. The low absolute numbers of SAEs precluded any exposure trend. Collectively, these analyses support selection of the High dose without an anticipated systemic exposure-related safety penalty.

Table 2.7.2-5. Any TEAE and injection-site reactions by steady-state exposure quartile (active-treated subjects)

Exposure group (C<sub>avg,ss</sub>)	Any TEAE, %	Injection-site reaction, %
Q1 (<7 µg/mL)	46.1	5.6
Q2 (7–14 µg/mL)	43.7	6.4
Q3 (14–24 µg/mL)	40.9	7.3
Q4 (>24 µg/mL)	38.2	8.1

Overall TEAE frequency declined across increasing exposure, mirroring the lower disease-activity-driven event burden in better-controlled, higher-exposure subjects (placebo reference 47.6%); only injection-site reactions rose modestly with exposure. No positive systemic exposure-toxicity gradient was identified.

2.7.2.3.6 Intrinsic Factors

Population PK covariate analysis identified body weight and serum albumin as the intrinsic factors most associated with TILA-278 exposure, with baseline inflammatory/disease burden contributing additionally.

• Body weight. Higher body weight was associated with higher clearance and volume (allometric relationship), yielding lower exposure in heavier subjects. Across the studied weight range the resulting exposure differences remained within the range associated with effective target coverage at the High dose, supporting fixed (flat) SC dosing without weight-based adjustment.
• Serum albumin. Lower serum albumin — a marker of more active/severe disease and protein loss — was associated with higher clearance and lower exposure, consistent with observations for therapeutic antibodies in inflammatory bowel disease. This effect reinforces selection of a dose that maintains adequate trough coverage in patients with severe disease.
• Baseline disease activity (CRP, faecal calprotectin). Higher baseline inflammatory burden was associated with modestly higher clearance, directionally consistent with the albumin effect.
• Age, sex, and race. No clinically relevant effect on exposure was identified.
• Renal and hepatic impairment. Dedicated organ-impairment studies were not conducted, consistent with regulatory expectations for a monoclonal antibody that is not renally excreted or hepatically metabolized as intact protein; mild-to-moderate renal or hepatic impairment categories represented in the popPK dataset showed no meaningful effect on exposure, and no dose adjustment is anticipated.
• Prior biologic exposure. A randomization stratification factor; no effect on PK was identified, and efficacy was consistent across the stratum.

Overall, the identified intrinsic-factor effects were modest and mitigated by selecting the higher, target-saturating dose; none warrant a dosing adjustment.

2.7.2.3.7 Extrinsic Factors

• Concomitant medications for UC. Aminosalicylates, corticosteroids, and immunomodulators (thiopurines/methotrexate) permitted per protocol showed no PK interaction with TILA-278. Concomitant immunomodulator use was associated with a lower incidence of treatment-emergent ADA (Section 2.7.2.4.1).
• Drug-drug interaction potential. As an IgG1 antibody, TILA-278 is not a substrate, inhibitor, or inducer of CYP enzymes or drug transporters, so direct pharmacokinetic DDIs are not expected. A theoretical therapeutic-protein–drug interaction exists whereby normalization of pro-inflammatory cytokine tone (via TL1A antagonism) could partially reverse cytokine-mediated CYP suppression and alter exposure of sensitive CYP substrates; the anticipated magnitude is small, and standard monitoring is advised when initiating or discontinuing TILA-278 in patients receiving narrow-therapeutic-index CYP substrates.
• Injection site. No clinically meaningful effect of injection site (abdomen, thigh, upper arm) on bioavailability or exposure was identified.
• Food. Not applicable to systemic exposure of an SC-administered antibody.

2.7.2.4 Special Studies

2.7.2.4.1 Immunogenicity and Its Impact

Immunogenicity was assessed using the validated tiered strategy described in Section 2.7.2.1 (screening, confirmatory, titre, and NAb). Treatment-emergent ADA developed in approximately 10.4% of TILA-278-treated subjects overall, with a higher incidence in the Low-dose group (12.9%) than the High-dose group (7.9%); NAb were confirmed in approximately 2.8%. The inverse relationship between dose/exposure and ADA incidence is consistent with greater and more sustained target coverage and higher circulating drug concentrations at the High dose promoting relative tolerance and reducing assay detection of low-level ADA. Titres were generally low, and a substantial proportion of responses were transient.

Impact on PK. Persistent, higher-titre ADA were associated with increased clearance and an approximately 25–30% reduction in trough concentrations; ADA status was retained as a covariate on clearance in the popPK model. Because the High dose maintains trough concentrations well above those associated with near-maximal response, this ADA-related exposure reduction did not translate into a clinically meaningful loss of target coverage in most High-dose subjects.

Impact on efficacy. Clinical remission rates were similar in ADA-positive and ADA-negative subjects at the High dose, whereas a modest reduction was observed in ADA-positive Low-dose subjects, consistent with the smaller exposure margin at the Low dose.

Impact on safety. ADA status was not associated with hypersensitivity, anaphylaxis, or injection-site reactions; injection-site reaction rates were comparable between ADA-positive and ADA-negative subjects. Concomitant immunomodulator use was associated with lower ADA incidence.

Collectively, the immunogenicity profile is favourable and further supports selection of the higher dose, which minimizes both ADA incidence and the clinical impact of any ADA that develop.

2.7.2.4.2 Cardiac Safety / QTc Assessment

TILA-278 is a large-molecule monoclonal antibody with no expected interaction with cardiac ion channels and no small-molecule metabolites. In accordance with the ICH E14/S7B Q&A framework for biologics, a dedicated thorough QT study is not warranted; the rationale rests on the absence of a plausible direct proarrhythmic mechanism for an antibody and is supported by the absence of a cardiovascular safety signal in TILA278-201 and in nonclinical safety pharmacology (cynomolgus monkey; Module 2.6.2). No QTc liability is anticipated.

2.7.2.5 Dose and Regimen Selection for Phase 3

The recommended Phase 3 induction dose is the TILA-278 High regimen (450 mg SC at Weeks 0, 2, 4, and 8). The rationale integrates the full clinical pharmacology package:

1. Efficacy is exposure-driven and near-plateau at the High dose. Clinical remission was strongly dose-ordered (placebo 0.7%, Low 16.2%, High 37.3%), and E-R modeling places the High-dose C_avg,ss (≈28 µg/mL) on the upper, flattening portion of the concentration-response curve (EC50 ≈12 µg/mL), whereas the Low dose sits on the steep, ascending portion with incomplete target coverage.
2. Target engagement supports the High dose. The High dose maintains >90% suppression of free TL1A together with robust IL-22-pathway activation across the dosing interval, whereas the Low dose provides incomplete and less sustained coverage.
3. Safety does not penalize the higher dose. No positive systemic exposure-dependent increase in TEAEs or SAEs was observed, and the overall TEAE rate at the High dose (38.4%) did not exceed that of the Low-dose (46.3%) or placebo (47.6%) groups. The only exposure-related finding was a modest increase in mild, self-limited injection-site reactions (8.1% High vs 6.0% Low), which did not lead to discontinuation and does not constitute a tolerability limitation.
4. Immunogenicity favors the higher dose. Treatment-emergent ADA were less frequent at the High dose, and the higher exposure margin buffered the modest ADA-related reduction in trough concentrations, preserving efficacy.
5. Intrinsic-factor robustness. The higher dose maintains adequate trough coverage across the range of body weight and serum albumin (including patients with severe, low-albumin disease), supporting fixed SC dosing without weight- or covariate-based adjustment.

For maintenance, a less frequent SC regimen (e.g., every 4 or every 8 weeks) targeting a trough concentration at or above that associated with sustained near-maximal response will be confirmed in the Phase 3 maintenance study, with the popPK/E-R model used to project maintenance exposures.

2.7.2.6 Overall Conclusions

TILA-278 exhibits the clinical pharmacology expected of an SC bispecific IgG1 antibody with dual TL1A-antagonist and IL-22 receptor-agonist activity: slow SC absorption, limited distribution, and parallel linear plus saturable target-mediated elimination, with exposure increasing approximately dose-proportionally across the clinical range as target-mediated clearance saturates. Efficacy in moderate-to-severe UC is exposure-driven and dose-ordered, with the High dose achieving near-maximal, well-tolerated response supported by near-complete TL1A neutralization and active IL-22-pathway agonism. No positive systemic exposure-dependent safety signal was identified; injection-site reactions, modestly more frequent at higher exposure, were the principal drug-attributable finding and were mild and self-limited. Immunogenicity was low and clinically manageable, with the higher dose minimizing both ADA incidence and impact. Intrinsic and extrinsic factors produced only modest exposure effects that do not require dose adjustment, and no QTc liability is expected. These data provide a coherent, quantitatively supported basis for advancing the TILA-278 High dose into the Phase 3 program.